Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly in lung transplant recipients (LTRs). Active CMV infection, including CMV pneumonitis, is associated with acute rejection episodes and is a recognized risk factor for chronic rejection (bronchiolitis obliterans syndrome) through poorly understood mechanisms. Donor+/Recipient(D+R-)- mismatched LTRs are at highest risk for CMV disease and demonstrate increased mortality. Moreover, the pathogenesis of active CMV infection and factors associated with clinical severity, such as pneumonitis remain poorly understood. The central hypothesis of this proposal is that both viral replication in the allograft and the host adaptive T cell response regulate the development of CMV pneumonitis and its clinical severity. Our preliminary data show that CMV viral load is higher in the lung airways (bronchoalveolar lavage;BAL) compared to the plasma during primary infection. Therefore, In SA1 we will further validate that replication is increased in the allograft compared to the blood during primary infection. We will also test our hypothesis that BAL viral loads are increased in LTRs with pneumonitis compared to those without. We will also determine whether BAL viral loads are higher with worse clinical severity, using a novel acute lung allograft dysfunction grading system that we have developed. Because we detect a massive influx of CMV-specific CD8+ T cells into the lung airways during pneumonitis, we will further determine in SA2 whether the magnitude of the host CD8+ response to CMV is increased during pneumonitis, and whether the CD8+ T cell response positively correlates with BAL and/or plasma viral loads and acute allograft dysfunction during primary infection. These CMV-specific immune studies are already being conducted in D+R- LTRs by the PI under an R21 award (R21 AI072537-01A1). The PI, John McDyer, MD, is a K08 awardee, transplant pulmonologist, and immunologist, who is strongly committed to understanding pathogenesis of CMV infection and disease in lung transplant recipients. He has assembled an expert team of co-investigators/consultants in transplant infectious disease, biostatistics, and post-transplant lung pathology for this project. This award will provide a foundation for novel translational work in a robust human primary infection model of CMV in LTRs to address these clinically relevant issues. PUBLIC HEALTH RELEVANCE: Solid organ transplantation, including lung transplantation, saves many lives each year. Cytomegalovirus (CMV) is the most common infection in solid organ transplant recipients, particularly lung transplant recipients, and is associated with increased risk for both acute and chronic rejection, and increased mortality, though it is unclear why. Understanding CMV replication in conjunction with the host immune response to CMV infection, and clinical measures of severity in susceptible lung transplant recipients may improve our detection of CMV infection, as well as potentially impact treatment strategies and long-term outcomes in all solid organ transplant recipients.